Background: Patients (pts) with advanced NSCLC without EGFR-activating mutations (EGFRm) have limited treatment options after failure of molecularly targeted therapies or platinum-based chemotherapy (PBC) with or without immunotherapy (IO). HER3-DXd is an antibody drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. We previously published efficacy and safety data from a study of HER3-DXd in EGFRm NSCLC after failure of EGFR tyrosine kinase inhibitor (TKI) therapy. Here we present results in pts without EGFRm who progressed after PBC ± IO treatment. Methods: This ongoing phase 1 dose expansion study included a cohort of pts with advanced NSCLC without EGFRm who received prior PBC ± IO (NCT03260491). Pts with stable brain metastases were eligible, as were pts with non-EGFR oncogenic alterations and prior targeted therapy. The primary endpoint was confirmed ORR by blinded independent central review (BICR) per RECIST v1.1; secondary endpoints included DOR, PFS, and safety. Results: At the Mar 26, 2021, data cutoff, 47 pts had been treated with HER3-DXd 5.6 mg/kg IV every 3 wk; 17 pts had an identified driver genomic alteration (4 KRAS and 1 NRAS mutations, 4 EGFR Ex20ins, 3 ROS1 and 2 ALK fusions, and 3 other). Median age was 62 y (range, 29-79 y); 53% of pts were female; 17% had squamous NSCLC. Median follow-up was 9.5 mo (range, 3.7-19.1 mo). Median number of prior anticancer regimens in the advanced setting was 3 (range, 0-8). Median treatment duration on study was 4.1 mo (range, 0.7-13.6 mo); treatment was ongoing in 11 pts (23%) at data cutoff. Confirmed ORR by BICR was 28% (13/47 pts; 95% CI, 16%-43%; 13 PRs, 22 SD). Median DOR was 5.7 mo (95% CI, 3.7-10.7 mo) and median PFS was 5.4 mo (95% CI, 3.9-12.7 mo). Among pts with identified driver genomic alterations, 35% (6/17) had a confirmed response by BICR, including 3 of 5 pts with KRAS/NRAS mutations and 2 of 2 with ALK fusions. Among pts without identified driver genomic alterations, 23% (7/30) had a confirmed response by BICR. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (26%), thrombocytopenia (15%), and fatigue (15%). Drug-related interstitial lung disease by central adjudication occurred in 4 pts (9%; 0 grade ≥3). Four pts (9%) had TEAEs associated with treatment discontinuation. No drug-related deaths occurred. Conclusions: These data show promising clinical activity in pts with NSCLC without EGFRm, including pts with other identified driver genomic alterations. Updated results from this study will be presented. The overall safety profile was similar to that previously reported in pts with EGFRm NSCLC. A phase 2 study of HER3-DXd in pts with EGFRm NSCLC after failure of EGFR TKI and PBC is ongoing (NCT04619004). Clinical trial information: NCT03260491.